High-dimensional therapeutic inference in the focally damaged human brain

See Thiebaut de Schotten and Foulon (doi:10.1093/brain/awx332) for a scientific commentary on this article. Though consistency across the population renders the extraordinarily complex functional anatomy of the human brain surveyable, the inverse inference—from common functional maps to individual behaviour—is constrained by marked individual deviation from the population mean. Such inference is fundamental to the evaluation of therapeutic interventions in focal brain injury, where the impact of an induced structural change in the brain is quantified by its behavioural consequences, inevitably refracted through the lens of lesion-outcome relations. Current therapeutic evaluations do not incorporate inferences to the individual outcome derived from a detailed specification of the lesion anatomy, relying only on reductive parameters such as lesion volume and crudely discretised location. Examining 1172 patients with anatomically registered focal brain lesions, here we show that such low-dimensional models are highly insensitive to therapeutic effects. In contrast, high-dimensional models supported by machine learning dramatically improve sensitivity by leveraging complex individuating patterns in the functional architecture of the brain. The failure to replicate in humans positive interventional effects in experimental animals is thus revealed to have a remediable inferential cause, forcing a radical re-evaluation of therapeutic inference in the human brain.